This invention relates to topically administrable ophthalmic and otic formulations of ciprofloxacin and dexamethasone. The formulations of the present invention are suspensions that have excellent physical stability and are characterized by their easy and ready resuspendibility. Specifically, the invention relates to stable suspension formulations of ciprofloxacin and dexamethasone that lack a nonionic tonicity agent, such as glycerol or mannitol.
Spanish Patent Application No. 2,065,846 A1 (Feb. 16, 1995) discloses topically administrable ophthalmic and otic antibiotic/steroid combination products. Examples 1-3 illustrate ophthalmic suspension formulations containing certain drug combinations with excipients including nonionic polymers and nonionic surfactants. Example 1 is a formulation of clobetasone and lomefloxacin that contains a nonionic tonicity agent (glycerin). Example 2 is a formulation of fluoromethalone and norfloxacin that contains an ionic tonicity agent (sodium chloride). Example 3 is a formulation of ciprofloxacin and dexamethasone that contains a nonionic tonicity agent (mannitol).
U.S. Pat. Nos. 5,540,930 and 5,747,061 disclose topically administrable steroid suspension formulations that contain a nonionic polymer, a nonionic surfactant and a nonionic tonicity agent. The patents are directed toward "stable suspensions of water-insoluble steroid drugs of particle sizes .ltoreq.15 .mu.m, which remain in such a state so as to allow for immediate suspension, when desired, even after extended periods of settling" (see the '061 patent's Abstract). The patents are based on a finding that "[u]nexpectedly, common tonicity agents such as aqueous solutions containing 0.9% NaCI, 0.1% EDTA, or phosphate buffer, even in concentrations as low as 1 mM, can not be employed to provide stable aqueous suspensions of corticosteroids such as [loteprednol etabonate (LE)]" ('061 patent, Col. 2, lines 52-56).
The '061 patent is aimed at formulations that solved a need for "aqueous suspensions of corticosteroids such as LE which can be formulated without agglomeration" (Col. 2, lines 57-59). The '061 patent's formulations contain (A) a soft steroid such as LE present as particles preferably having a mean diameter of less than about 15 microns, (B) a nonionic polymer as a suspending agent, (C) a nonionic surfactant and (D) a nonionic tonicity agent. The '061 patent defines a "soft" drug as a biologically active chemical component characterized by predictable in vivo metabolism to non-toxic derivatives after it provides its therapeutic effect. The '061 patent teaches that "[i]t is essential that these components (A)-(D) be nonionic insofar as possible since it has now been discovered that the presence of ions is the major cause of caking" (Col. 3, lines 51-53). Nonionic diols such as glycerin or mannitol "rather than the commonly used sodium chloride" are identified as the preferred tonicity agents (see Col. 3, lines 53-56). The nonionic tonicity agent is preferably present in an amount of about 0.5 to 10% by weight.